CS241074B2 - Method of thiazolidine derivatives preparation - Google Patents

Abstract

New thiazolidine compounds of the formula (I) having anti-ulcer activity are disclosed: <IMAGE> (I) wherein Ar is a 2-furyl or a phenyl, naphthyl or pyridyl group optionally substituted by one or more C1-4-alkyl, C1-4-alkoxy, halo-C1-4-alkoxy, dihalomethyl, trihalomethyl, hydroxyl or nitro groups or by a group of the formula (II), <IMAGE> (II) wherein Y is nitrogen or CH; Z is cyano or carbamoyl if Y is nitrogen, and represents a nitro group if Y is CH. Also disclosed are several processes for preparing the new compounds as well as pharmaceutical compositions and method of treatment employing same.

Description

(54) A method for preparing thiazolidine derivatives

New thiazolidine derivatives of formula (I) are prepared.

CH-Ar

Y-2 (I) by reacting a nitrogen-substituted 1-amino-2-thiol derivative of formula III

HS-CH2-CH2-NH-CH2-Ar (III) with a compound of formula IV \

C-Y-Z (IV) and optionally converting a substituent in a compound of Formula I to another substituent.

The novel thiazolidine derivatives of formula I are valuable anti-ulcer agents.

The invention relates to a process for the preparation of novel thiazolidine derivatives which are suitable for the preparation of pharmaceutical compositions. In particular, the invention relates to a process for the preparation of novel thiazolidine derivatives of the general formula I

Z * CH 2 Ar r-N

У-Z (I) where means

Ar is 2-furyl or phenyl, naphthyl or pyridyl, optionally substituted with at least one halogen atom, at least one C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkoxy, dihalomethyl group or a trihalomethyl group, a hydroxyl group and / or a nitro group or a group of the general formula II p-M ', (II) in which:

Y is N or —CH,

Z is cyano or carbamoyl when Y is nitrogen or nitro when Y is —CH.

The novel thiazolidine derivatives of the formula I are valuable anti-ulcer agents, i.e. they are highly effective for the treatment of gastrointestinal ulcers.

The novel thiazolidine derivatives of formula (I) are of great therapeutic importance, since the number of people suffering from gastric or duodenal ulcers is constantly increasing both in absolute and proportional terms. Although numerous pharmaceutical compositions for the treatment of ulcers range from 4,5-dihydrothiazoles to relatively new 4-aryl-4-hydroxy-4,5-dihydrothiazoles (U.S. Pat. No. 4,143,148), these compounds are substantially structurally different from the compounds of the invention .

With respect to the mechanism of action, known anti-ulcer agents have a very varied action. Newly discovered histamine-H2 antagonists such as cimetidine [N-cyano-N'-methyl-N '-2- (5-methylimidazol-4-yl / methylthio) ethylguanidine] form a balanced group and are characterized by inhibiting selectively histamine-induced gastric acid secretion. From tricyclic 6H-pyrido- (2,3-b) - (1,4) benzodiazepines, pirenzepine is known to be [5,11-dihydro-11- ([4-methyl-1-piperazinyl] acetyl) -6H- pyrido] (2,3-b) - (1,4) benzodiazepin-6-one, as a substance that inhibits ulcer formation as much as atropine, but is free of other anticholenergic effects (e.g., inhibition of peristalsis, impaired eye accommodation) , salivation inhibition). Various antacids that do not inhibit gastric acid overproduction bind excess acid; they are also generally used.

The novel thiazolidine derivatives of the general formula (I) prepared according to the invention have a broad spectrum of activity and are therefore suitable for the treatment of gastrointestinal ulcers which arise as a result of various pathological mechanisms and can be used successfully for treating ulcers caused by non-steroidal anti-inflammatory agents. Certain preferred compounds of these anti-ulcer agents, for example 3-benzyl-2-cyanoiminothiazolidine, have another important advantage since, unlike known histamine-H2 receptor antagonists, they do not have functional groups from which undesired carcinogenic N-nitroso compounds can be formed in the body.

There are several possibilities for the chemical classification of the novel compounds of formula (I) prepared by the process of the invention. According to the nomenclature used in Chemical Abstracts, these compounds may be considered as substituted carboxylic acid derivatives such as cyanamide, urea and the like which have a heterocyclic radical as a substituent. On the other hand, they are compounds, for example compounds containing a substituent of the formula —CHNO2 in the 2-position, whose heterocyclic moiety can be considered as the main structural element to which, for example, the aforementioned side chain is attached as a substituent. For uniformity, all compounds of Formula I are referred to herein as thiazolidine derivatives, which clearly indicates the unsaturated nature of the side chain at position 2 (e.g., the cyanoimine and nitromethylene chains).

Compounds of formula (I) wherein each symbol is as defined above are prepared by the process of the invention by reacting an N-substituted 1-amino-2-thiol derivative of formula (III)

HS-CH2-CH2-NH-CH2-Ar (III) wherein

Ar is as defined above, with a compound of formula IV

L

\

C - Y - Z / L (IV) where

Y and Z are as defined above and L is a leaving group, and optionally in a compound of formula (I) wherein Ar, Y and Z are as defined above, one substituent is converted to another substituent within the meaning of the individual symbols known per se way.

The group R represents the various liberated groups used in the art preferably forms a dithiocarboxyl group with a carbon atom.

The process is carried out in the presence of a solvent, the progress of the reaction being recorded and controlled by monitoring the evolution of gas. Depending on the solubility of the reactants, water and optionally an aqueous alcohol, acetone, ether, acetonitrile, hydrocarbons or chlorinated hydrocarbons are preferably used as solvents. The reaction temperature can be varied within wide limits, depending on. the reactants used and the. the solvent used. To ensure a suitable reaction rate, the reaction is preferably carried out at a temperature of 40 to 80 cc. The by-product formed in the reaction depends on the nature of the group released and is preferably methylmercaptan which escapes from the reaction mixture in the form of vapors, the reaction product can be easily released from the mixture, for example by filtration if the product crystallizes or evaporates the reaction mixture.

. The secondary mercaptoalkylarylmethylarines of the general formula (III) used as starting material can, for example, be prepared by the corresponding reaction. oxo compounds (aldehyde or ketone) with a 1-amino-2-thiol compound and reduction of the thiazolidine derivative thus obtained with a complex metal hydride (see J. Org. Chem. 27, 4712, 4763 (1963)).

Conversion of a substituent of a compound of formula I to another substituent of that compound within the meaning of the individual substituents of a compound of formula I can be carried out in a manner known per se. way. For example, a cyano group meaning symbool. Z can be hydrolyzed to a carbamoyl group in an aqueous acidic medium. If a compound of formula I wherein Z is cyano is reacted with an acid such as hydrochloric acid in a non-aqueous medium, an immediately separable iminochloride is formed from which the desired compound of formula I wherein Z is carbamoyl can be prepared, alkalization in aqueous medium.

As another example of converting a substituent of a compound of formula I to another substituent, the conversion of optional substituents on the Ar group is by known methods. Thus, a methoxy group in a compound of formula I wherein Ar is a methoxy substituted phenyl group can be converted to a hydroxyl group by reacting the compound with a boron bromide in an organic. solvent and basifying the reaction mixture. Similarly, the hydroxyl group in the compound of formula (I) may be converted to other substituents within the meaning of the above-mentioned meanings of the individual symbols by known methods.

A preferred representative compound of formula (I) is 3-benzyl-2-cyanoiminothiazolidine (compound A). The results of the pharmacological tests carried out with this compound are described below, but it is noted that the other compounds of formula I also have significant activity.

The pharmacological activity of the novel compounds of the formula I is investigated in the following ways:

Shay test

This assay was first described by Shay et al. in 1945 (Gastroenterology 56, pp. 5-13, 1945). Female H-Wlstar rats (120-150 g) were fasted for 24 hours. Water is available at will. Pylorus is ligated to the animals under mild ether anesthesia. The test substance is administered during the operation. Four hours after treatment, the animals are sacrificed with a large portion of ether. The stomach is excised and cut at the point of great curvature. The volume and pH of the contents are determined, and in certain cases the production of hydrochloric acid is titrated.

Aspirin-induced gastric ulcer test

Non-periodic anti-inflammatory agents are known to induce gattrointetinal ulcers to some extent (Drugs and Peptic Ulcer, Ed. Pfeiffer, CRC Press, New York, 1982). To a large extent, anti-ulcer compounds are tested by the so-called aspirin-inducing ulcer assay. For this test, female rats weighing 120. up to 150 grams are starved for 24 hours. They can consume water at will. Gastric ulcer is induced by oral administration of 100 mg / kg aspirin (as a suspension in Tween 80). The test compound is administered concomitantly with aspirin and also orally. Rats are sacrificed with a large portion of ether 4 hours after treatment. The stomach is excised and dissected at the point of great curvature. The contents are washed out slightly and the haemorrhagic disturbances of the glandular surface are calculated. The results of the test are evaluated and the number of gastric ulcers or rats that do not have ulcers is determined.

Intestinal ulcers induced by indomethacin

Of the non-steroidal anti-inflammatory agents, indomethacin not only induces gastric ulcers as a side effect but can also largely cause intestinal ulceration.

Depending on the dose, intestinal ulceration can be lethal, peritonitis kills the animal due to intestinal perforation.

(a) Indomethacin-induced lethal intestinal ulceration

Non-fasted female H-Wistar rats weighing 120-150 g each were treated orally with 15 mg / kg of indomethacin (as a suspension in Tween 80) .The test substance is administered orally following indomethacin administration, under which conditions intestinal ulceration (ulceration) occurs in 48 to 72 hours The so-called inflatable technique described by Ezer and Szporny (J. Pharm. Pharmacol., 27, 866, 1975) is used to assess the development of intestinal ulcers in order to quantitatively record the progress of ulceration. The wall, expressed in kPa, decreases gradually in parallel with the ulceration process.

b) Indomethacin-induced non-lethal ulceration

Non-fasted female H-Wistar rats weighing 120-150 g were each treated with an oral administration of 7.5 mg / kg indomethacin to induce intestinal ulceration that did not result in death. After 4 hours, 24 hours and 48 hours, and indomethacin treatment, the rats were orally dosed with the test substance. Rats are sacrificed 24 hours after the last treatment and 72 hours after indomethacin ulcer induction. ce is evaluated by an inflatable test.

Gastric necrosis induced by absolute alcohol

This method was introduced by A. Robert (Gastroenterology 77, 433 (1979)) along with the term cytoprotection. Female H-Wistar rats weighing 120-150 g are fasted for 24 hours. They can consume water at will. The test compound is administered orally 30 minutes prior to the administration of ethanol in an amount of 0.5 ml / 100 g body weight of the probe. Two hours later, rats are sacrificed with a large portion of ether. The stomach is excised and dissected at the point of greatest curvature. The etching induced by the administered ethanol is localized to the stomach corpus as numerous linear haemorrhagic bands of necrotized tissue. The etching length in millimeters is measured (Derlanko and Long, Proc. Soc. Exp. Biol. And Med. 166, p. 394, 1981) and the length of the median etching on the stomach is determined. The degree of protection is expressed as a percentage with respect to the control test.

Investigation of the above-described assays has shown that 3-benzyl-2-cyamminothiazolidine (compound A), which is a preferred representative compound of formula (I) prepared by the process of the invention, appears to be a very potent anti-ulcer compound in these pharmacological tests. This compound inhibits gastric acid secretion in the Shay rat at a low dose (ED 50 = 5.3 mg / kg i.p.). Aspirin-induced gastric ulceration by concomitant administration of Compound A orally (ED50 - 2.1 mg / kg p.o.) is also inhibited. Compound A is also effective in the absolute alcohol necrosis assay introduced recently by Robert et al. (Gastroenterology 77: 433-443, 1979). It is particularly noted that the concomitant administration of Compound A inhibits indomethacin-induced intestinal ulceration. This result is important because cimetidine, one of the most potent anti-ulcer agents, cannot inhibit intestinal ulceration induced by indomethacin (Ezer and Szporny, J. Pharm. Pharmacol., 33, 250-251, 1981; Der Soldato et al. Brit. J. Pharmacol., 67, 33-37, 1979 (GL Kaufman et al. Proc. Soc. Exp. Biol. 151, 512-514 (1970)). This is supported by the clinical results obtained by Mitchell and Sturrock (Brit. Med. J. 284, 731 (1982)), which demonstrate that co-administration of cimetidine and indomethacin results in perforations in rheumatic patients who simultaneously suffer from gastric ulcers. Anticholinergic compounds (for example Propantheline, Gastrixon) cannot prevent indomethacin-induced intestinal ulceration.

The results of the above tests are summarized in Tables 1 to 6. The abbreviations used have the following meanings:

n - number of animals tested b. w. - weight

t. s - strength

Table 1

Inhibitory action of Compound A on gastric acid secretion in Shay rats (ligation of pylorus: 4 hours)

Treatment n Dose mg / kg i.p. Acid secretion μπιοί НС1 / / 100 g b. W. Inhibice% Note Control 20 May - 429 - Compound A 5 1,25 436 0 Compound A 10 2.5 358 17 Compound A 10 5.0 301 30 ED50 = 5.3 Compound A 20 May 10.0 0 100 ALIGN! Compound A 5 25.0 0 100 ALIGN!

Table 2

Effect of Compound A, administered by various routes, on inhibition of gastric acid secretion (Shay rats, 4 hours)

Method of administration n dose mg / kg Stomach acid secretion ml / 100 g, b.w. volume inhibition pH 15 min. before surgery i. p. 5 10 2.5 42% 3.7 15 min. before surgery s. c. 5 10 2.8 35% 1.5 15 min. before surgery p. c 5 10 2.3 47% 4.1 Control 5 - 4.3 - 1

Table 3

Inhibition of aspirin-induced gastric ulcers by concomitant treatment with Compound A

Očetrení n Dose mg / kg p. Number of ulcers per stomach ulcer inhibition% Ulcerated animal environment% Aspirin (control) 20 May 100 ALIGN! 15.7 + 3.0 - 0 Aspirin + Compound A 10 100 + 1.5 9,5 **) 40 0 Aspirin 4-Compound A 17 100 + 3.0 6,8 *) 57 23 Aspirin 4-Compound A 17 100 + 6.0 4.7 *) 71 29 Aspirin 4-Compound A 14 100 + 12.0 2,2 *) 86 66 Aspirin 4-Compound A 17 100 + 25.0 2,3 *) 85 41

P <0.05

P <0.1 ED50 2.1

Table 4

Dose-dependent inhibition of indomothacial-induced intestinal ulceration with concomitant administration of compound A

Treatment n Dose p. 0. Intestinal strength Intestinal wall resistance in% of normal Note mg / kg wall 72 hours after kPa treatment Untreated control 30 - 31.2 + 0.7 100 ALIGN! * / p less than Indomethacin 16 15 Dec 6.2 ± 1.6 20 May 0.01 with respect to the group imidometha- ninu Indomethacin 4-Compound A 10 15 + 15 16.2 + 2.7 52 Indomethacin 4-Compound A 10 15 + 25 25.9 + 2.5 83 * Indomethacin 4-Compound A 20 May 15 + 50 30.4 + 7.1 97 * ED100 = 50 Indomethacin 4-cimetidine 10 15 + 150 6.3 + 3.4 21 Indomethacin 4- Na-salicylate 10 15 + 25 17.8 + 2.3 57 * ED100 = 50 Indomethacin 4- Na-salicylate 10 15 + 50 31.2 + 0.7 100 *

Table 5

Indomethacinern-induced (7.5 mg / kg p. O.) Procedure of non-lethal intestinal ulceration in case of cimetidine and additional treatment with compound A

Treatment 4, 24, 48 hours after indomethacinern treatment n Dose pg mg / kg Intestinal wall strength 72 hours after indomethacin kPa treatment Group untreated individuals 30 - 31.2 + 0.7 AND Indomethacin 32 7.5 25.0 + 1.5 В Indomethacin + cimetidine 12 7.5 + 3 X 50 24.8 + 1.0 C Indomethacin + cimetidine 12 7.5 + 3 X 100 ALIGN! 26.6 4- 1.4 D Indomethacin + Compound A 10 7.5 + 3 X 25 23.8 + 2.7 F Indomethacin + Compound A 10 7.5 + 3 X 50 33.6 -I- 5.3 G

A - В less than 0.05 В - C, D, F N. S.

В - G less than 0,01

Table 6

Cytoprotective action of Compound A against gastric necrosis induced by absolute alcohol

Treatment n Dose mg / kg p. Medium etching length (mm / stomach) Cytoprotection (%) Note Control 112 - 82,4+ 5 - EDo - 2.8 Compound A 6 1.5 52.5 + 19 37 *) Compound A 12 3.0 34.8 + 10 58 *) Compound A 12 6.0 29,9+ 9 64 *) Compound A 13 12.0 32,9+ 5 60 *) Compound A 6 25.0 18,0+ 8 78 *) Cimetidine 5 6.0 46.0 + 10 44 *) Cimetidine 5 12.0 63.0 + 18 24 Cimetidine 10 25.0 55.0 + 12 33 EDso not listen- Cimetidine 15 Dec 50.0 34.0 + 10 59 *) table Cimetidine 12 100.0 47.0 + 16 43 ^х )

Cimetidine

*) p <0.01 relative to control

The values in Table 1 demonstrate that Compound A acts to reduce gastric acid secretion in a dose-dependent manner. It is very important that Compound A effectively inhibits gastric juice secretion even when administered orally, as evidenced by the rat-Shay values reported in Table 2.

Compound A inhibits the formation of aspirin-induced gastric ulcers when co-administered with aspirin in a dose-dependent manner. Induction of gastric ulcers of 20 mg / kg oral dose of indomethacin is also effectively inhibited. The results are shown in Table 3.

Table 4 illustrates the inhibition of fatal indesthacin-induced fatal intestinal ulcer administered at 15 mg / kg by the oral route.

Compound A exhibits dose-dependent effects on intestinal ulcer induction indomethacinern (15 mg / kg p.o.).

The results obtained with so-called non-lethal intestinal ulceration seem particularly important. In these tests, treatment was started 4 hours after indomethacin ulcer induction (7.5 mg / kg p.o.). Thus, post-treatment was performed 4 hours, 24 hours and 48 hours after indomethacinern treatment. The values in Table 5 show that cimetidine and ranitidine are ineffective in this assay, while compound A can normalize intestinal wall strength in a dose-dependent manner.

Compound A is effective against gastric necrosis induced by absolute alcohol. According to the results shown in Table 6, cytoprotection is dose-dependent.

Pharmacological testing suggests that Compound A has a broad field of activity, broader than cimetidine, for example.

Example 1

2.21 g (13.2 mmoles) of N-benzylcysteamine are boiled in 10 ml of ethanol [boiling point is

90 ° C / 26.66 Pa) and 1.93 g (13.5 mmol) of cyaniminodithiocarboxylic acid as dimethyl ester. Intense gas evolution ends in 15 minutes. The mixture is kept overnight at 0 ° C and then filtered to give 2.57 g (89.6% of theory) of 3-benzyl-2-cyaniminothiazolidine, m.p. 102-104 ° C. Recrystallization does not change the melting point.

Analysis for:

C11H11N3S (217.29) calculated:

% C, 60.80;% H, 5.10;% N, 19.34.

14.76% S, found:

% C, 60.98;% H, 5.02;% N, 19.57.

14.96% S.

IR spectrum (KBr):

2190 cm-1 —C = N

1570 cm ^_ 1 = C = N— (wide)

NMR Spectrum (CDCl5):

3.38 ppm m (2) —S — CH2—

3.85 ppm m (2) - N - CH 2 - (heterocyclic)

4.65 ppm S (2) = N - CH 2 - (phenyl)

7.38 ppm S (2) - Ar - H

In the same way, the following compounds are prepared from the corresponding starting materials:

2-cyanimino-3- (4-chlorobenzyl) thiazolidine melting point: 131-133 ° C analysis for:

C11H10ClN3S (251.74) calculated:

% C, 52.48;% H, 4.00;% N, 16.69;

% C, 52.72;% H, 4.18;% N, 16.49.

IR spectrum (KBr):

2185 cm ^-1 —C = N

1560 cm1 = C = N—

1092 cm ¹ —Ar — Cl

Nuclear Magnetic Resonance Spectrum (CDCl3 + DM.sub.2) - .delta.

3.3 ppm m (2) —S — CH2—

3.8 ppm m (2) = N - CH2 - (heterocyclic)

4.5 ppm S (2) = N - CH 2 - (CeH + Cl)

7.12 ppm S (2) - Ar - H

2-cesniimiiio-3- (3,4-сиск1огЬеп7у1) thiazolidine analysis for:

C11H9Cl2N5S (286.18) calculated:

% C, 46.16;% H, 3.17;% S, 11.21.

H, 3.18; H, 11.22.

IR spectrum (KB +):

2190 cm -1 —CsN

1570 cm -1 = C — N—

1060 cm @ -1

NMR Spectrum (CDCl3):

3,4 ppm m (2) -S-CI-I2-

3.7 ppm m (2) = N — CH2 · - (Heterocyclic)

4.56 ppm s (2) = N - CH 2 - (3,4-dichlorophenyl) 6.9 to 7.5 ppm m (3) - Ar - H

2-kzdiidtno-3 ·· (4-nitroredzyl) thiazolidide melting point: 171 ° C analysis for:

C11H10N4O2S (262.29):

calculated:

% C, 50.37;% H, 3.84;% N, 21.36.

% C, 50.36;% H, 3.94;% N, 21.46.

IR spectrum (KBr):

2190 cm @ -1 —C = N

1575 cm -1 = C = N—

1505 cm ⁴ , 1334 _cm -1 —NO2

NMR Spectrum (CDCl3 + DMSO-d6):

3.4 ppm m (2) - S - CH 2 -

3.8 ppm m (2) —N — CH2—

4.65 ppm s (2) = -N-CH2-CbH4 p-NO2

7.35 ppm d (2) - Ar - H (2.6)

8.05 ppm d (2) -Ar-H (3.5)

2-cadimido-3- (2-hydroxy-5-nitrolidinyl) thiazolidine melting point: 253-255 ° C analysis for:

C11H10N4O3S (278.29) calculated:

% C, 47.47;% H, 3.62;% N, 20.13.

% C, 47.78;% H, 3.71;

mp 130-132 ° C

IR spectrum (KBr):

3100 cm ^-1 (wide) —OH

2190 cm ^{-1 1} -C ⁵ N

1575 cm ¹ ^ C = N—

1522, 1338 cm -1 —NO?

NMR Spectrum (CDCl 3 + DMSO-ck):

3.4 ppm m (2) —S — CH2—

3.8 ppm m (2) —N — CH2 (heterocyclic)

4.54 ppm s (2) = N — СНг- (2-ОН, 5-NO2-СеНз)

6.88 ppm t (1) —Ar — H (3)

8.00 ppm m (2) - Ar - H (4.6) - 9 ppm b (1) - OH

2-cyanimino-3- (3-hydroxybenzyl) thiazolidine melting point: 126-128 ° C analysis for:

C11H11N3OS (233.29) calculated:

C 56.63, H 4.75, S 13.75,

18.02% N, found:

C 56.70, H 5.07, S 13.75,

17.83% N.

IR spectrum (KBr):

3260, 1230 cm ^{-1 -} OH

2190 cm @ -1 - feN

1570 cm -1 = C = N—

NMR Spectrum (CDCl3 + DMSO-d6):

3.3 ppm m (2) —S — CH2—

3.7 ppm m (2) - = N - CH 2 - (heterocyclic)

4.48 ppm s (2) -N-CH 2 - (hydrophenyl)

4.48 ppm s (2) - N - CH 2 - (hydroxyphenyl)

6.5 - 7.4 ppm m (4) - Ar - H

8.6 b (l) - OH

2-cylamino-3- (1-naphthylmethyl) thiazolidine melting point: 167 ° C analysis for:

C15H1.3N3S (267.34):

calculated:

% C, 67.39;% H, 4.90;% N, 15.72;

12,00% S, found:

% C, 67.32;% H, 4.80;% N / 15.78;

11.96% S.

IR spectrum (KBr):

2190 cm ^-1 —C = N

1580 cm- ¹ = C- = N—

NMR Spectrum (CDCl3 + DMSO-d6):

3.2 ppm m (2) —S — CH2—

3.6 ppm m (2) = N - N - (heterocyclic)

4.92 ppm s (2) - N - CH 2 - (naphthyl)

7.0 - 7.9 ppm m (7) - Ar - H

3.3 ‘- (1,4-xylylene) bis- (2-cyanimino thiazolidine) melting point: 275-278 ° C analysis for:

CifiHieNeS? (356.47) calculated:

53.91% C, 4.52 «/ o II, 17.99% S,

23.58% N, found:

C 53.70, H 4.78, S 17.85,

23.37% N.

IR spectrum (KBr):

2180 cm @ -1 = c

1570 cm ^-1 = C — N—

NMR Spectrum (DMSO-d 6):

3,4 ppm m (4) —S — CH 2 -

3.7 ppm m (4) - = N - CH 2 - (heterocyclic)

4.50 ppm S (4) - N - CH 2 - (phenylene)

7.18 ppm S (4) - Ar - H

2-cyanimino-3- (6-methyl-2-pyridylmethyl) thiazolidine, or 2 - ((2-cyanimino-3-thiazolidinyl) methyl] -6-methylpyridine, m.p. 114 DEG C. analysis for:

C11H12N1S (232.30) calculated:

% C, 56.87;% H, 5.20;% N, 24.12;

% H, 5.12;% N, 24.18.

IR spectrum (KBr):

2190 cm @ -1

1570 cm -1 -CN

NMR Spectrum (CDCl3):

2.48 ppm s (3) - Ру — СНз

3.3 ppm m (2) —S — CH2—

3.9 ppm m (2) —N — CH2—

4.6 ppm s (2) - N - CH 2 - (Py)

6.9 ppm d (2) —Py 2,5-H

7.4 ppm 6 (1) —Py 4-H

2-cyanimino-3- (6-dichloromethyl-2-pyridyl-241074 methyl) thiazolidine or 2 - [[2-cyanimino-3-thlazolidinyl] methyl] -6-dichloromethylpyridine melting point: 122 ° C analysis for:

C11H10Cl2N1S (301.19) calculated:

% C, 43.86;% H, 3.34;% S, 10.64.

% C, 43.91;% H, 3.46;

IR spectrum (KBr):

2180 cm —C-N

1560 cm @ -1 —CH — Cl

NMR Spectrum (CDCl3):

3.34 ppm t (2) —S — CH2—

3.97 ppm t (2) —N — CH2—

4.62 ppm s (2) = N - CH 2 - [phenyl]

6.50 ppm s (1) —Py — CH—.

7.0 - 7.8 ppm m (3) —Py — H

3-benlyl-2- (carbamoylimino) thiazolidine melting point: 148 ° C analysis for:

CnH18SOS [235.31) calculated:

% C, 56.15;% H, 5.57;% N, 17.86.

% H, 5.46;% N, 18.10.

IR spectrum (KB ’|:

3320, 3260 cm '—NH2

1645 cm ”1 = c — o

1540 cm ”1 = C — N—

NMR Spectrum (CDCl3 + DMSO-d6):

3.05 ppm t (2) —S — CH2—

3.50 ppm t (2) = N - CH 2 - (heterocyclic)

4.75 ppm. s (2) = N - CH 2 - (phenyl)

5.60 ppm b (2) -NH 2

7.32 ppm s (5) - Ar - H

2-Cyanoimino-3- (2-furylmethyl) thiazolidine Melting point: 124-125 ° C Found:

N, 20.38; S, 15.44.

IR spectrum [KBr]:

2185 cm-1 —C = N

1570 cm -’- - c — N—

1238 cm ”’ = c — O — C =

795 cm ´Ar — H

NMR Spectrum (CDCl3):

3.3 ppm m - S - CH2 -

3.7 ppm m - = N - CH 2 - (heterocyclic)

4.57 ppm 3-N-CH2-Ar '

6.30 ppm d - Ar - (3,4) H

7.30 ppm m - Ar - (5) H

2-Cyanimino-3- (4-methylbenzyl) thiazolidine Melting point: 102-104 ° C Analysis for:

C12H15N3S [231.31) calculated:

% C, 62.66;% H, 5.66;% S, 13.85.

% C, 62.16;% H, 5.52;% S, 13.96.

IR spectrum [KBr]:

2190 cm- 'C = N

1590 cm ”’. c. N -

1260 cm- - S — CHa—

792 cm ’—Ar

NMR Spectrum (CDCl3):

2.31 ppm with —CH3

3.30 ppm m —S — CH2—

3.70 ppm m —N — CH2— (heterocyclic)

4.54 ppm s == N — CH2— (phenylene)

7.10 ppm with —Ar — H

3- (2-Furylmethyl) -2-nitrethylethiazolidine m.p. 190-192 ° C

IR spectrum (KBr):

1543, 1340 cm ”´ —NO2

1640 cm ”’ = c = C =

3130, 757 cm ”furan = C — H

1243 cm ”’ = C — 0 — C = furan ring

NMR Spectrum (CH2-COOH):

analysis for:

CgHgNaOS (207.25) calculated:

N, 20.28; N, 15.47;

3.7 ppm t - S - CH 2 -

4.6 ppm t - N - CH 2 -

5.7 ppm s = N - CH 2 - (C 1 H 3 O)

6.3 ppm b = CH - NO 2

6.5 ppm m furan 3.4 H

7.5 ppm n furan 5 H

18

2-Cyanimino-3- (4-hydroxybenzyl) thiazolidine, m.p. 175-177 ° C

IR spectrum (KBr):

2190 cm-1 - cN

1570 cm -1 · C = N—

3210 cm @ -1 —OH

1610, 840 cm -1 _Ar

NMR Spectrum (CDCL):

3.4 ppm m —S — CH2 —

3.7 ppm m = N - CH2 -

4.5 ppm with —Ar — CH2

6.9 ppm q-Ar-H

9.47 ppm s —CH

Example 2

3-Benzyl-2-miromethylenthiazolidine

Under reflux in 50 ml of ethanol. It boils for 1 hour 3.34 g (20 millimoles) of N-benzylcysteamine and 3.3 g of 1,1-bismethylthio-2-nitroethylene. Gas evolution ends after boiling for 20 minutes. The mixture was cooled and the precipitated product was collected by filtration. 4.52 g of product are obtained, m.p. 136 DEG-138 DEG. Recrystallization from 140 ml of ethanol yields 4.08 of purified product, m.p. 139 ° C.

Analysis for:

C 11 H 11 N 2 O 2 S (236.30) calculated:

% C, 55.91;% H, 5.12;% N, 11.86.

H, 4.99; N, 11.89.

IR spectrum (KBr):

1633 cm -1 = c — C =

1535, 1354 cm -1 —NC2

NMR Spectrum (CDCl3):

3.10 ppm t - S - CH2 -

3.80 ppm t —N — CH2 — (heterocyclic)

4.43 ppm s = N - CH 2 - (C 6 H 6)

6.97 ppm with —CH =

7.0-7.3 ppm m-Ar-H

Example 3

2-Cyanimino-3- (4-methoxybenzyl) thiazolidine

3.65 g (23.5 mmoles) of cyaniminodithiocarboxylic acid in the form of dimethyl ester (94% purity) are boiled in 30 ml of ethanol until completion of the development of methylmercaptan.

5.91 g (30 mol) of N- (4-methoxybenzyl) cysteamine. The reaction mixture was evaporated and the crystalline residue was recrystallized from 15 ml of isopropanol. 5.35 g (92% of theory) of 2-cyanimino-3- (4 (methoxyphenyl) -thiazolidine, m.p. 99-102 DEG C.) are obtained.

Analysis for:

C12H17N3OS (247.31) calculated:

% C, 58.28;% H, 5.30.

% C, 58.35;% H, 5.17.

IR spectrum (KBr):

2840 cm-1 —O — CH3

2185 cm &lt; -1 &gt; -1-N

1570 cm -1 - ₌ c = N—

1608, 814 cm ^@ -1 - ^Ar

NMR Spectrum (CDCl3):

3.3 ppm m - S - CH2 -

3.7 ppm m = N - CH2 -

3.75 ppm · s —O — CH3

4.43 ppm s = N-CH2 - (CaHs)

6.90 ppm q-Ar-H

N - (4-methoxybenzyl) cysteamine used as starting material is prepared by reacting 4-methoxybenzaldehyde with cysteamine and reducing 2- (4-methoxyphenyl) thiazolidine (m.p. 93-94 ° C after recrystallization from isopropanol) with sodium borohydride in isopropanol (J). Org. Chem., 27, 4712 (1962). N- (4-Methoxybenzyl) cysteamine is an oil with a boiling point of 120 to 125 ° C / 1 mmHg.

Example 4

Preparation of a pharmaceutical composition

The tablet formulation is prepared from the following ingredients (for 1000 tablets):

g 3-benzyl-2-cyaniminothiazolidine (active substance) g starch g milk sugar g talc g g polyvinyl pyrrolidone g magnesium stearate g colloidal silicic acid

200 g

The finely ground active ingredient is mixed with milk sugar and talc, the mixture is kneaded with.

polyvinylpyrrolidone solution and passed through a sieve. The granules are dried, mixed with magnesium stearate and colloidal silicic acid and compressed into 1000 tablets each weighing 0.2 g.

Claims (1)

SUBJECT A process for the preparation of thiazolidine derivatives of the general formula I / O (I) wherein Ar is 2-furyl or phenyl, naphthyl or pyridyl, optionally substituted with at least one halogen atom, at least one C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkoxy, dihalomethyl group or a trihalomethyl group, a hydroxyl group and / or a nitro group or a group of the formula II Г— ~ N (II) I INVENT in which Y is N or CH Z cyano or carbamoyl when Y is nitrogen and nitro, when Y is CH, characterized in that the N-substituted 1-amino-2-thiol derivative of formula III is reacted HS-CH2-CH2-NH-CH2-Ar (III) wherein Ar is as defined above, with a compound of formula IV L \ C = Y — Z / L (IV) where Y and Z are as defined above and L is a leaving group, and optionally converting a substituent in a compound of formula I wherein Ar, Y and Z are as defined above to another substituent as defined herein.